Throughout this application various publications are referenced. Full citations for these publications may be found at the end of the specification. The disclosure of these publications are hereby incorporated by reference in order to more fully describe the state of the art to which this invention pertains.
Hyaline Membrane Disease (HMD) and Respiratory Distress Syndrome (RDS) are synonymous terms denoting the clinical condition of pulmonary dysfunction in premature infants. The disease is attributable to the absence of surface active material (surfactant) which lines the air-alveolar interface in the lung and prevents collapse of the alveoli during respiration. Current therapy is predominantly supportive. However, recent clinical trials indicate that one promising therapy is the instillation of bovine-derived surfactant into the lungs of the neonate.
Surface tension in the alveoli of the lung is lowered by a lipoprotein complex called pulmonary surfactant. This complex consists of phospholipid and 5-10% protein (King, 1982). The protein fraction of the surfactant is composed of nonserum and serum proteins. The major surfactant associated protein is reportedly a 35,000 dalton nonserum, sialoglycoprotein (Shelly et al., 1982; Bhattacharyya et al, 1975; Sueishin and Benson 1981; King et al, 1973, Katyal & Singh, 1981). This protein reportedly seems to be important for the normal function of the pulmonary surfactant (King et. al., 1983; Hawgood et.al., 1985). It is present in reduced amounts in amniotic fluid samples taken shortly before the birth of infants who subsequently develop respiratory distress syndrome (Katyal and Singh, 1984; Shelly et al., 1982; King et al., 1975). Recently the biosynthesis of a 35,000 dalton protein in normal human lung tissue was studied and in an invitro translation reaction, proteins of 29 and 31 kDa were identified as the primary translation products (Floros et al., 1985). A 35 kDa protein also accumulates in the lungs of patients with alveolar proteinosis (Battacharyya and Lynn, 1978, Battacharyya and Lynn, 1980a). This protein has the same electrophoretic mobility, immunological determinants and peptide mapping as the 35 kDa protein from normal human broncho-alveolar lavage material (Phelps et al., 1984; Whitsett et al., 1985 ).
In addition to the above mentioned proteins, the presence in rat lungs of a number of lower molecular weight surfactant-associated proteins has recently been reported. See D. L. Wang, A. Chandler and A. B. Fisher, Fed. Proc. 44(4): 1024 (1985), Abstract No. 3587 (ca. 9000 dalton rat protein) and S. Katyal and G. Singh, Fed. Proc. 44(6): 1890 (1985), Abstract No. 8639 (10,000-12,000 dalton rat protein).
Finally, a Feb. 6, 1985 press release from California Biotechnology Inc. reports the cloning and "detailed manipulation" of "the gene encoding human lung surfactant protein." However, the press release does not characterize that protein or describe the "detailed manipulations." Two other reports of possible surfactant-related proteins have also been published recently, namely, J. A. Whitsett et al., 1986, Pediatr. Res. 20:460 and A. Takahashi et al., 1986,
The present invention relates to a new group of proteins recovered and purified from lung lavage of patients with alveolar proteinosis, methods for obtaining the proteins, corresponding recombinant proteins, antibodies to the proteins for use in diagnostic products, compositions containing the novel proteins, and methods for using the compositions, e.g. in the treatment of infants afflicted with conditions such as Respiratory Distress Syndrome (RDS), as a drug delivery vehicle in the administration of other therapeutic materials to the lungs or other organs and in the treatment of adult RDS, which can occur during cardiopulmonary operations or in other situations when the lungs are filled with fluid and natural pulmonary surfactant production and/or function ceases. While it is possible that one or more of the proteins described hereinafter is similar or identical to proteins discussed in the abovementioned papers, the exact relationship of the protein of this invention to prior proteins cannot at present be confirmed given the inadequacies of the prior disclosures with respect to amino acid or nucleotide sequence data, surfactant activity of prior proteins and the like.